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EGFR (Epidermal growth factor receptor) inhibitor and preparation method and use thereof

An alkyl and amino technology, applied in the field of drug synthesis, can solve problems such as poor selectivity, limited dosage, and reduced affinity and drug resistance between drugs and targets

Active Publication Date: 2016-04-20
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The drug resistance of half of the patients is due to the secondary mutation of the EGFR gatekeeper gene residue T790M, which reduces the affinity of the drug and the target and produces drug resistance, resulting in tumor recurrence or disease progression
[0006] In view of the importance and prevalence of this mutation in drug resistance in lung cancer EGFR-targeted therapy, several drug R&D companies (Pfizer, BI, AZ, etc.) are trying to develop second-generation small molecule EGFR inhibitors, by inhibiting the EGFRT790M mutant strain To achieve the treatment of such drug-resistant lung cancer patients, but all ended in failure due to poor selectivity
Even though afatinib has been approved by the FDA for the treatment of lung cancer, it is only used for the first-line treatment of patients with EGFR activating mutations; for patients with EGFRT790M mutations, because afatinib has a stronger inhibitory effect on wild-type EGFR, causing severe Skin and gastrointestinal toxicity limited dosing, did not show therapeutic effect

Method used

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  • EGFR (Epidermal growth factor receptor) inhibitor and preparation method and use thereof
  • EGFR (Epidermal growth factor receptor) inhibitor and preparation method and use thereof
  • EGFR (Epidermal growth factor receptor) inhibitor and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0068] Preparation of intermediates

[0069] 1. Intermediate 1: Preparation of 4-fluoro-2-methoxy-5-nitroaniline

[0070]

[0071] 4-Fluoro-2-methoxynitrobenzene (10 g, 58.44 mmol) was dissolved in methanol, 1 g of palladium / carbon was added, replaced by hydrogen, and reacted under hydrogen atmosphere for three days. Filtrate, collect the filtrate, and distill methanol off to obtain an oily crude product. Concentrated sulfuric acid was added to the crude product at 0°C to dissolve all the solids in the mixture, and potassium nitrate (5.91 g) was added in batches. The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water, NaHCO was added 3 , adjust pH6.0-8.0. The aqueous phase was extracted three times with dichloromethane, and the organic phase was collected and dried. The organic solvent was evaporated, and the residue was separated and purified by column chromatography to obtain 4-fluoro-2-meth...

Embodiment 1

[0096] Embodiment 1: N-(5-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-2-((2 Preparation of -(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0097]

[0098] The first step: the preparation of 2-isopropylmercapto-3-nitropyridine

[0099]

[0100] Put 2-fluoro-3-nitropyridine (500mg, 3.52mmol), potassium carbonate (973mg, 7.04mmol) in a 100mL round bottom bottle, add 15ml of DMF, add isopropylthiol (0.36mL, 3.87mmol) under stirring ), the mixture was reacted at room temperature for 1 hour, and the reaction solvent was rotated off after the reaction was completed. The crude product obtained was washed with water, extracted with ethyl acetate, dried and concentrated, and then column chromatography to obtain the product 2-isopropylmercapto-3-nitro Pyridine (660 mg, 95% yield).

[0101] LC-MS: t=4.31min, 198.9 (M+H + );

[0102] 1 HNMR (400MHz, CDCl 3 )δ8.61(dd, J=4.8, 1.6Hz, 1H), 8.40(dd, J=8.4, 1.6Hz, 1H), 7.10(dd, J=8.4...

Embodiment 2

[0131] Example 2: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(isopropylsulfonyl)pyridin-3-yl )amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide preparation

[0132]

[0133] N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidine -2-yl)amino)-4-methoxyphenyl)acryloylamide The preparation method is the same as the fourth to eighth steps of Example 1.

[0134] LC-MS: t R =2.02min, 569.3([M+H] + );

[0135] 1 HNMR (400MHz, CDCl 3 )δ9.81(s,2H), 9.01(m,2H), 8.57(d,1H), 8.02(s,1H), 7.24-7.35(m,3H), 6.79(s,1H), 6.10(m ,2H), 5.48(d,1H), 3.88(s,3H), 3.80(m,1H), 2.93(br,2H), 2.73(s,3H), 2.36(m,8H), 1.43(d, 6H).

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Abstract

The present invention discloses an EGFR (Epidermal growth factor receptor) inhibitor and a preparation method and use thereof. In particular, the present invention relates to compounds of N-(5-((4-((2-(alkyl-substituted sulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino)-phenyl) acryloyl amide analogs shown as a formula (I), wherein substituents of the formula (I) are as defined in the specification. The series of compounds can inhibit the activity of a L858R EGFR mutant, a T790MEGFR mutant and an exon 19 deletion activated mutant, can be used for treating diseases alone or partly actively mediated by an EGFR mutant, has broad application in medicines for prevention and treatment of cancer particularly non-small cell lung cancer, and is expected to be developed into a new generation EGFR inhibitor.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to an EGFR inhibitor, namely N-(5-((4-((2-(alkyl substituted sulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino )-phenyl)acrylamide analogs and their preparation and application. Background technique [0002] EGFR (Epidermal Growth Factor Receptor) is a member of the transmembrane protein tyrosine kinase erbB receptor family. EGFR can form homodimers on the cell membrane by binding to its ligands, such as epidermal growth factor (EGF), or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4) . The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in cells. These intracellular signaling pathways play important roles in cell proliferation, survival and anti-apoptosis. Dysregulation of EGFR signaling pathway, including increased expression of ligands and re...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/506A61P35/00A61P35/02
Inventor 孙兴义危明松崔媛媛仝朝龙张福军包如迪喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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